The goal of this program is to use specific myelin antigens to alter differentiation of autoreactive T cells, and to study the cellular and molecular mechanisms by which myelin antigens or altered forms of myelin antigens may shift the balance of pro-inflammatory cytokines from responding autoreactive T lymphocytes. To this end, three projects have been constructed: Project 1 (Kuchroo, V.K. Project Leader) will study the mechanism by which altered peptides of myelin proteolipid protein can either inhibit or enhance the autoimmunity of the CNS using the EAE model. In this project native encephalitogenic and altered peptide ligand (APL) specific TCR transgenic mice will be utilized to understand the mechanism by which APLs can shift the cytokine balance. Project 2 (Weiner, H.L Project Leader) will study the effect of feeding myelin antigens, altered forms of myelin antigens or co-polymer (Copaxone ) on the regulation of EAE. In this project Dr. Weiner will study the effect of changing the affinity of the peptides that have been altered either at the MHC residue or at the T cell contact residue, and determine the effect of these altered peptides in inhibiting or enhancing oral tolerance. In addition, this project will study the mechanisms of induction of regulatory T cells (Th3 type cells that produce TGF-beta) that are induced following oral administration of antigen, and also will study enhancement by oral tolerance by oral cytokines (IL-4, IL-10, IFN- tau). Project 3 (Hafler, D.A. Project Leader) will examine the effect of APLs in the induction of regulatory cytokines from human MBPp85-99 reactive T lymphocytes. This project examines whether APLs induce a new population of Th2 autoreactive cells or if they differentially signal pathogenic T cells and alter their differentiation. In addition, this project will examine whether Copaxone acts as an APL for MBP reactive T cell using combinatorial peptide libraries. The use of combinatorial libraries will also be used to define preferential antigens recognized by Copaxone reactive T cells. Projects 1 & 3 will have a consortium with Dr. S. Burakoff's laboratory at Dana Farber Cancer Institute, Boston to study the intracellular signaling events in T lymphocytes following crosslinking of TCRs with cognitive versus APLs. An immunopathology core will support projects 1 and 2. The three interdependent projects address a common theme: development of antigen specific, non-toxic therapy for the treatment of the CNS autoimmune disease-MS. Study of basic mechanisms in animal models and immune responses in MS patients as outlined above will help understanding towards reaching this goal.